DOCSLIB.ORG

Identification of SPRED2 As a Novel Regulator of Hypothalamic-Pituitary-Adrenal Axis Activity and of Body Homeostasis“ Eigenständig, D.H

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of SPRED2 As a Novel Regulator of Hypothalamic-Pituitary-Adrenal Axis Activity and of Body Homeostasis“ Eigenständig, D.H Identification of SPRED2 as a Novel Regulator of Hypothalamic‐Pituitary‐Adrenal Axis Activity and of Body Homeostasis Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Julius-Maximilians-Universität Würzburg vorgelegt von Melanie Ullrich aus Karlstadt Würzburg 2014 Eingereicht bei der Fakultät für Biologie am: ____________________________ Mitglieder der Promotionskommission: Vorsitzender: ____________________________ 1. Gutachter: ____________________________ 2. Gutachter: ____________________________ Tag des Promotionskolloquiums: ____________________________ Doktorurkunde ausgehändigt am: ____________________________ Eidesstattliche Erklärung Hiermit erkläre ich an Eides statt, dass ich meine Dissertation mit dem Titel „Identification of SPRED2 as a Novel Regulator of Hypothalamic-Pituitary-Adrenal Axis Activity and of Body Homeostasis“ eigenständig, d.h. insbesondere selbstständig und ohne Hilfe einer kommerziellen Promotionsberatung angefertigt habe und keine anderen als die von mir angegebenen Quellen oder Hilfsmittel benutzt habe. Des Weiteren versichere ich, dass ich die Gelegenheit zum Promotionsvorhaben nicht kommerziell vermittelt bekommen habe und dass ich insbesondere nicht eine Person oder Organisation eingeschaltet habe, die gegen Entgelt Betreuer bzw. Betreuerinnen für die Anfertigung von Dissertationen sucht. Ich erkläre außerdem, dass die Regeln der Universität Würzburg über gute wissenschaftliche Praxis eingehalten wurden, dass die Dissertation weder in gleicher noch in ähnlicher Form bereits in einem anderen Prüfungsverfahren vorgelegen hat und dass ich akademische Grade weder bereits früher erworben noch zu erwerben versucht habe. Würzburg, 2014 _______________________ Melanie Ullrich Die vorliegende Arbeit wurde unter Betreuung von Herrn Prof. Dr. Kai Schuh am Physiologischen Institut der Julius-Maximilians-Universität Würzburg angefertigt. Teile dieser Dissertation wurden bereits in wissenschaftlichen Publikationen oder in Form von Abstracts zur Präsentation auf wissenschaftlichen Kongressen veröffentlicht. Publikationen Wissenschaftliche Publikationen Benz, P.M., Merkel, C.J., Offner, K., Abeßer, M., Ullrich, M., Fischer, T., Bayer, B., Wagner, H., Gambaryan, S., Ursitti, J.A., Adham, I.M., Linke, W., Feller, S.M., Fleming, I., Renné, T., Frantz, S., Unger, A., Schuh, K. (2013): Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy. Cell Commun Signal. 11:56. Ullrich, M., Bundschu, K., Benz, P.M., Abesser, M., Freudinger, R., Fischer, T., Ullrich, J., Renné, T., Walter, U., and Schuh, K. (2011): Identification of SPRED2 (Sprouty-related protein with EVH1 domain 2) as a negative regulator of the hypothalamic-pituitary-adrenal axis. J Biol Chem. 286 (11): 9477-88. Ullrich, M. and Schuh, K. (2009): Gene trap - knockout on the fast lane. Methods Mol Biol. 561, 145-159. Johne, J., Blume, C., Benz, P.M., Pozgajová, M., Ullrich, M., Schuh, K., Nieswandt, B., Walter, U., and Renné, T. (2006): Platelets promote coagulation factor XII-mediated proteolytic cascade systems in plasma. Biol Chem. 387, 173-78. Bundschu, K., Knobeloch, K.-P., Ullrich, M., Schinke, T., Amling, M., Engelhardt, C.M., Renné T., Walter, U., and Schuh, K. (2005): Gene disruption of Spred-2 causes dwarfism. J Biol Chem. 280 (31), 28572-80. Wissenschaftliche Publikationen in Revision Fischer, T., Rokita, A.G., Benz, P.M., Fissler, B., Ullrich, M., Abeßer, M., Seibold, S., Reichle, J., Lars, S., Maier, L.S., Ritter, O., Seidlmayer, L.K., Zuern, C., Wohlschlaeger, J., Baba, H.A., Schuh, K.: ATIP1 is a suppressor of cardiac hypertrophy and modulates AT2-dependent signaling in cardiac myocytes. Andere wissenschaftliche Artikel in den Medien http://www.nationalgeographic.de/aktuelles/koerpereigene-stressbremse-entdeckt http://www.innovationsreport.de/html/berichte/biowissenschaften_chemie/stressbremse_versagt_172042.html http://derstandard.at/1297820667155/Forscher-identifizieren-Stressbremse Abstracts zur Präsentation auf wissenschaftlichen Kongressen Ullrich, M., Weber, M., Post, A., Popp, S., Guerrero, H., and Schuh. K. (2014): SPRED2 – a Critical Regulator of Synaptic Protein Expression and of Behavior? Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Mainz Augustin, A.M., Ullrich M., Abesser, M., and Schuh K. (2014): Antagonizing aldosterone reduces cardiac effects of SPRED2-deficiency only partially. Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Mainz Ullrich, M., Abesser, M., Augustin, A.M., and Schuh, K. (2013): SPRED2 - A Novel Modulator of Cardiac Hypertrophy and Electrical Conduction in the Heart? Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Heidelberg Ullrich, M., Abesser, M., Augustin, A.M., and Schuh, K. (2012): SPRED2 - A Novel Modulator of Cardiac Hypertrophy and Electrical Conduction in the Heart? Posterpräsentation, Jahrestagung des Deutschen Zentrums für Herzinsuffizienz, Kloster Banz Ullrich, M. and Schuh, K. (2012): Physiological Role of SPRED2 in the Mammalian Heart. Vortrag, Begutachtung des DZHI-Projekts B10, ESAB-Meeting des DZHI, Würzburg Ullrich, M. and Schuh, K. (2011): Identification of SPRED2 as a negative regulator of the HPA axis. Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Regensburg Bundschu, K., Schuh, K., Walter, U., and Ullrich, M. (2010): SPRED2 (Sprouty-related protein with EVH1 domain 2) regulates bone growth and hypothalamic-pituitary-adrenal hormone secretion. Posterpräsentation, EMBO Meeting, Barcelona Ullrich, M., Bundschu, K., Walter, U., and Schuh, K. (2010): Dysregulated hypothalamic- pituitary-adrenal (HPA) hormone secretion in SPRED2-deficient mice. Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Kopenhagen. Ullrich, M., Walter, U., and Schuh, K. (2009): Dysregulated hypothalamic-pituitary-adrenal (HPA) hormone secretion in SPRED2-deficient mice. Posterpräsentation, Jahrestagung der Deutschen Vereinten Gesellschaft für Klinische Chemie und Laboratoriumsmedizin, Leipzig Ullrich, M., Bundschu, K., Freudinger, R., Gattenloehner, S., Walter, U., and Schuh, K. (2009): Dysregulation of hypothalamic-pituitary-adrenal hormone secretion in SPRED2-deficient mice. Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Giessen. Ullrich, M., Freudinger, R. Bundschu, K., Walter, U., and Schuh, K. (2008): Phenotype puzzle in Spred-2-deficient mice. Posterpräsentation, Jahrestagung der Deutschen Vereinten Gesellschaft für Klinische Chemie und Laboratoriumsmedizin, Mannheim Ullrich, M., Bundschu, K., Freudinger, R., Gattenloehner, S., Walter, U., and Schuh, K. (2008): Hormone, ion, and fluid imbalance in Spred-2-/- mice. Posterpräsentation, Graduate School of Life Sciences, Würzburg Ullrich, M., Bundschu, K., Walter, U., and Schuh, K. (2008): Phenotype puzzle in Spred-2- deficient mice. Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Köln. Ullrich, M., Bundschu, K., Gattenloehner, S., Walter, U., and Schuh, K. (2007): Dwarfism and kidney failure in Spred-2-deficient mice. Posterpräsentation, Jahrestagung der Deutschen Physiologischen Gesellschaft, Hannover. Ullrich, M., Bundschu, K., Walter, U., and Schuh, K. (2006): Spred-2 deficiency results in dwarfism and kidney failure. Vortrag und Posterpräsentation, Experimental Biology Meeting, San Francisco Ullrich, M., Schmitteckert, E., Renné, T., Walter, U., and Schuh, K. (2006): Generation of a system for thrombocyte-specific gene deletion. Posterpräsentation, Jahrestagung der Gesellschaft für Thrombose und Hämostase, Basel Preise und Auszeichnungen „1. Posterpreis“ auf der Jahrestagung des Deutschen Zentrums für Herzinsuffizienz (DZHI) in Kloster Banz „FEPS Best Poster Award” auf dem European Young Physiologists Symposium im Rahmen der Physiologentagung in Kopenhagen „Travel Award” im Rahmen des Experimental Biology Meetings in San Francisco Das Genie beginnt die schönen Werke, aber nur die Arbeit vollendet sie. Joseph Joubert Meiner Familie Danksagung An dieser Stelle möchte ich mich bei all den Personen bedanken, ohne die die Durchführung und Vollendung meiner Dissertation nicht möglich gewesen wäre: Mein größter Dank gilt Herrn Prof. Dr. Kai Schuh, der mir die Bearbeitung dieses Dissertationsthemas in seiner Arbeitsgruppe ermöglicht hat. Lieber Kai, du warst mir in all den Jahren ein ganz hervorragender Betreuer. Ich konnte sowohl in wissenschaftlicher als auch in menschlicher Hinsicht wirklich sehr viel von dir lernen. Ganz herzlichen Dank für die Freiheit sowohl bei der experimentellen als auch bei der schriftlichen Gestaltung dieser Arbeit, für deine stets offene Tür, für deine unerschöpfliche Diskussionsbereitschaft, für deine Geduld, deine Motivation und deinen Glauben an mich. Durch deine immerwährende Unterstützung konnte ich die Ergebnisse dieses schönen Projekts publizieren und als meine Doktorarbeit zu Papier bringen. Ein herzliches Dankeschön gilt auch Herrn Prof. Dr. Georg Krohne für die Bereitschaft, nach meiner Diplomarbeit auch meine Dissertation als Vertreter der biologischen Fakultät zu begutachten. Vielen Dank für die stets unkomplizierte Zusammenarbeit. Ganz besonders bedanken möchte ich mich bei allen aktuellen und ehemaligen Kolleginnen und Kollegen der AG Schuh. Lieben Dank an euch, Doreen, Krissi, Anne, Ruth, Priscilla, Carla, Feli, Chris, Constanze, Marco, Peter, Tobi, Hans und Robert für das stets konstruktive
Load more

Recommended publications
  • 14954 Spry2 (D3G1A) Rabbit Mab
    Revision 1 C 0 2 - t Spry2 (D3G1A) Rabbit mAb a e r o t S Orders: 877-616-CELL (2355) [email protected] 4 Support: 877-678-TECH (8324) 5 9 Web: [email protected] 4 www.cellsignal.com 1 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source/Isotype: UniProt ID: Entrez-Gene Id: WB, IP H M R Endogenous 35 Rabbit IgG O43597 10253 Product Usage Information 7. Sánchez, A. et al. (2008) Oncogene 27, 4969-72. 8. Frank, M.J. et al. (2009) Blood 113, 2478-87. Application Dilution 9. Yim, D.G. et al. (2015) Oncogene 34, 474-84. 10. Okur, M.N. et al. (2014) Mol Cell Biol 34, 271-9. Western Blotting 1:1000 11. Mason, J.M. et al. (2004) Mol Biol Cell 15, 2176-88. Immunoprecipitation 1:100 12. Edwin, F. et al. (2009) Mol Pharmacol 76, 679-91. 13. Fong, C.W. et al. (2003) J Biol Chem 278, 33456-64. Storage Supplied in 10 mM sodium HEPES (pH 7.5), 150 mM NaCl, 100 µg/ml BSA, 50% glycerol and less than 0.02% sodium azide. Store at –20°C. Do not aliquot the antibody. Specificity / Sensitivity Spry2 (D3G1A) Rabbit mAb recognizes endogenous levels of total Spry2 protein. Species Reactivity: Human, Mouse, Rat Source / Purification Monoclonal antibody is produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Pro71 of human Spry2 protein. Background The Sprouty (Spry) family of proteins are antagonists of receptor tyrosine kinase (RTK)- induced signaling (1, 2).
    [Show full text]
  • Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1201 Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina Focus on α2-Adrenergic and Endothelin Receptor Signaling Systems MOHAMMAD HARUN-OR-RASHID ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-9527-5 UPPSALA urn:nbn:se:uu:diva-281569 2016 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husagatan 03, Uppsala, Thursday, 19 May 2016 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Docent Per Ekström (Lund University). Abstract Harun-Or-Rashid, M. 2016. Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina. Focus on α2-Adrenergic and Endothelin Receptor Signaling Systems. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1201. 73 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9527-5. Müller cells are major glial cells in the retina and have a broad range of functions that are vital for the retinal neurons. During retinal injury gliotic response either leads to Müller cell dedifferentiation and formation of a retinal progenitor or to maintenance of mature Müller cell functions. The overall aim of this thesis was to investigate the intra- and extracellular signaling of Müller cells, to understand how Müller cells communicate during an injury and how their properties can be regulated after injury. Focus has been on the α2-adrenergic receptor (α2-ADR) and endothelin receptor (EDNR)-induced modulation of Müller cell-properties after injury.
    [Show full text]
  • Generation and Characterization of Spred-2 Knockout Mice
    Generation and Characterization of Spred-2 Knockout Mice Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Dr. med. Karin Andrea Bundschu (geb. Geis) aus Frankfurt/Main Würzburg 2005 Eingereicht am: .....…………………………………………………………….. Mitglieder der Promotionskommission: Vorsitzender: ...……………………………………………………………….. Gutachter: Prof. Dr. U. Walter Gutachter: Prof. Dr. G. Krohne Betreuer: Dr. Kai Schuh Tag des Promotionskolloquiums: …………………………………………… Doktorurkunde ausgehändigt am: …………………………………………… The present study was performed under supervision of Dr. Kai Schuh in the group of Prof. Dr. med. Ulrich Walter in the Institute of Clinical Biochemistry and Pathobiochemistry at the Julius-Maximilians-University of Würzburg. The dissertation was part of the MD/PhD program, organized by the IZKF of the University of Würzburg. Declaration: Hereby, I declare that the submitted dissertation was completed by myself and no others and that I have not used any sources or materials other than those enclosed. Moreover, I declare that the following dissertation has not been submitted further in this form or any other form and has not been used for obtaining any other equivalent qualification in any other organization. Additionally, other than this degree I have not applied or will attempt to apply for any other degree or qualification in relation to this work. Würzburg, (Dr. med. Karin Andrea Bundschu) In love for my husband Christoph and our son Sebastian Table of Contents
    [Show full text]
  • 2018 Abstract Book
    CONTENTS Table of Contents INFORMATION Continuing Medical Education .................................................................................................5 Guidelines for Speakers ..........................................................................................................6 Guidelines for Poster Presentations .........................................................................................8 SPEAKER ABSTRACTS Abstracts ...............................................................................................................................9 POSTER ABSTRACTS Basic Research (Location – Room 101) ...............................................................................63 Clinical (Location – Room 8) ..............................................................................................141 2018 Joint Global Neurofibromatosis Conference · Paris, France · November 2-6, 2018 | 3 4 | 2018 Joint Global Neurofibromatosis Conference · Paris, France · November 2-6, 2018 EACCME European Accreditation Council for Continuing Medical Education 2018 Joint Global Neurofibromatosis Conference Paris, France, 02/11/2018–06/11/2018 has been accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) for a maximum of 27 European CME credits (ECMEC®s). Each medical specialist should claim only those credits that he/she actually spent in the educational activity. The EACCME® is an institution of the European Union of Medical Specialists (UEMS), www.uems.net. Through an agreement between
    [Show full text]
  • Sprouty Proteins, Masterminds of Receptor Tyrosine Kinase Signaling
    CORE Metadata, citation and similar papers at core.ac.uk Provided by RERO DOC Digital Library Angiogenesis (2008) 11:53–62 DOI 10.1007/s10456-008-9089-1 ORIGINAL PAPER Sprouty proteins, masterminds of receptor tyrosine kinase signaling Miguel A. Cabrita Æ Gerhard Christofori Received: 14 December 2007 / Accepted: 7 January 2008 / Published online: 25 January 2008 Ó Springer Science+Business Media B.V. 2008 Abstract Angiogenesis relies on endothelial cells prop- Abbreviations erly processing signals from growth factors provided in Ang Angiopoietin both an autocrine and a paracrine manner. These mitogens c-Cbl Cellular homologue of Casitas B-lineage bind to their cognate receptor tyrosine kinases (RTKs) on lymphoma proto-oncogene product the cell surface, thereby activating a myriad of complex EGF Epidermal growth factor intracellular signaling pathways whose outputs include cell EGFR EGF receptor growth, migration, and morphogenesis. Understanding how eNOS Endothelial nitric oxide synthase these cascades are precisely controlled will provide insight ERK Extracellular signal-regulated kinase into physiological and pathological angiogenesis. The FGF Fibroblast growth factor Sprouty (Spry) family of proteins is a highly conserved FGFR FGF receptor group of negative feedback loop modulators of growth GDNF Glial-derived neurotrophic factor factor-mediated mitogen-activated protein kinase (MAPK) Grb2 Growth factor receptor-bound protein 2 activation originally described in Drosophila. There are HMVEC Human microvascular endothelial cell four mammalian orthologs (Spry1-4) whose modulation of Hrs Hepatocyte growth factor-regulated tyrosine RTK-induced signaling pathways is growth factor – and kinase substrate cell context – dependant. Endothelial cells are a group of HUVEC Human umbilical vein endothelial cell highly differentiated cell types necessary for defining the MAPK Mitogen-activated protein kinase mammalian vasculature.
    [Show full text]
  • SPRED2 (NM 181784) Human Tagged ORF Clone Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC212199L3 SPRED2 (NM_181784) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: SPRED2 (NM_181784) Human Tagged ORF Clone Tag: Myc-DDK Symbol: SPRED2 Synonyms: Spred-2 Vector: pLenti-C-Myc-DDK-P2A-Puro (PS100092) E. coli Selection: Chloramphenicol (34 ug/mL) Cell Selection: Puromycin ORF Nucleotide The ORF insert of this clone is exactly the same as(RC212199). Sequence: Restriction Sites: SgfI-MluI Cloning Scheme: ACCN: NM_181784 ORF Size: 1254 bp This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 SPRED2 (NM_181784) Human Tagged ORF Clone – RC212199L3 OTI Disclaimer: Due to the inherent nature of this plasmid, standard methods to replicate additional amounts of DNA in E. coli are highly likely to result in mutations and/or rearrangements. Therefore, OriGene does not guarantee the capability to replicate this plasmid DNA. Additional amounts of DNA can be purchased from OriGene with batch-specific, full-sequence verification at a reduced cost. Please contact our customer care team at [email protected] or by calling 301.340.3188 option 3 for pricing and delivery. The molecular sequence of this clone aligns with the gene accession number as a point of reference only. However, individual transcript sequences of the same gene can differ through naturally occurring variations (e.g.
    [Show full text]
  • Genome-Wide Association Study Meta-Analysis of European
    Molecular Psychiatry (2013) 18, 195–205 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp ORIGINAL ARTICLE Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder DT Chen1, X Jiang1, N Akula1, YY Shugart1, JR Wendland1, CJM Steele1, L Kassem1, J-H Park2, N Chatterjee2, S Jamain3, A Cheng4, M Leboyer3, P Muglia5, TG Schulze1,6, S Cichon7,MMNo¨then7, M Rietschel8, BiGS9 and FJ McMahon1 1Human Genetics Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MA, USA; 2Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Rockville, MA, USA; 3Inserm U955, Department of Psychiatry, Groupe Hospitalier Henri Mondor-Albert Chenevier, AP-HP, Universite´ Paris Est, Fondation FondaMental, Cre´teil, France; 4Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; 5Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 6Section on Psychiatric Genetics, Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-Universita¨t, Go¨ttingen, Germany; 7Institute of Neuroscience and Medicine, Juelich, Germany and Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany and 8Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of B750 000 high-quality genetic markers on a combined sample of B14 000 subjects of European and Asian-ancestry (phase I).
    [Show full text]
  • A Shared Molecular Mechanism Underlies the Human Rasopathies Legius Syndrome and Neurofibromatosis-1
    Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION it has been reported to function both upstream of and A shared molecular mechanism downstream from Ras (Wakioka et al. 2001; King et al. underlies the human 2005). Overexpression of Spred1 can increase Raf’s re- cruitment to the plasma membrane, where it associates rasopathies Legius syndrome with Ras without stimulating Raf activation (Wakioka and Neurofibromatosis-1 et al. 2001). Yet, this mechanism has never been fully refined and fails to explain how Spred1 prevents Raf ac- Irma B. Stowe,1 Ellen L. Mercado,1 tivation. A separate report suggests that Spred1 may pre- Timothy R. Stowe,2 Erika L. Bell,1 vent Ras activation, as evidenced by decreased Ras-GTP 3 3 levels when Spred1 is overexpressed (King et al. 2005). Juan A. Oses-Prieto, Hilda Herna´ndez, Heterozygous germline loss-of-function mutations have 3 1,4 Alma L. Burlingame, and Frank McCormick been identified in SPRED1 in Legius syndrome, a develop- 1 mental disorder that shares a number of phenotypes with Helen Diller Family Comprehensive Cancer Center, University Neurofibromatosis-1 (NF1) (Brems et al. 2007). Both syn- of California at San Francisco, San Francisco, California 94158, 2 dromes are characterized as rasopathies, congenital devel- USA; Department of Neurological Surgery, University of opmental syndromes caused by germline mutations that California at San Francisco, San Francisco, California 94143, affect the Ras/MAPK pathway. Legius syndrome has been USA; 3Department of Pharmaceutical Chemistry, University of characterized as a milder form of NF1, with individuals California at San Francisco, San Francisco, California 94143, USA displaying multiple cafe´-au-lait spots, axillary freckling, and macrocephaly, but lacking other common NF1 man- The Ras/mitogen-activated protein kinase (MAPK) path- ifestations such as Lisch nodules, neurofibromas, osseous way plays a critical role in transducing mitogenic signals lesions, or optic pathway gliomas.
    [Show full text]
  • Dissecting the Genetics of Human Communication
    DISSECTING THE GENETICS OF HUMAN COMMUNICATION: INSIGHTS INTO SPEECH, LANGUAGE, AND READING by HEATHER ASHLEY VOSS-HOYNES Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Epidemiology and Biostatistics CASE WESTERN RESERVE UNIVERSITY January 2017 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We herby approve the dissertation of Heather Ashely Voss-Hoynes Candidate for the degree of Doctor of Philosophy*. Committee Chair Sudha K. Iyengar Committee Member William Bush Committee Member Barbara Lewis Committee Member Catherine Stein Date of Defense July 13, 2016 *We also certify that written approval has been obtained for any proprietary material contained therein Table of Contents List of Tables 3 List of Figures 5 Acknowledgements 7 List of Abbreviations 9 Abstract 10 CHAPTER 1: Introduction and Specific Aims 12 CHAPTER 2: Review of speech sound disorders: epidemiology, quantitative components, and genetics 15 1. Basic Epidemiology 15 2. Endophenotypes of Speech Sound Disorders 17 3. Evidence for Genetic Basis Of Speech Sound Disorders 22 4. Genetic Studies of Speech Sound Disorders 23 5. Limitations of Previous Studies 32 CHAPTER 3: Methods 33 1. Phenotype Data 33 2. Tests For Quantitative Traits 36 4. Analytical Methods 42 CHAPTER 4: Aim I- Genome Wide Association Study 49 1. Introduction 49 2. Methods 49 3. Sample 50 5. Statistical Procedures 53 6. Results 53 8. Discussion 71 CHAPTER 5: Accounting for comorbid conditions 84 1. Introduction 84 2. Methods 86 3. Results 87 4. Discussion 105 CHAPTER 6: Hypothesis driven pathway analysis 111 1. Introduction 111 2. Methods 112 3. Results 116 4.
    [Show full text]
  • Understanding the Genetic Basis of Phenotype Variability in Individuals with Neurocognitive Disorders
    Understanding the genetic basis of phenotype variability in individuals with neurocognitive disorders Michael H. Duyzend A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2016 Reading Committee: Evan E. Eichler, Chair Raphael Bernier Philip Green Program Authorized to Offer Degree: Genome Sciences 1 ©Copyright 2016 Michael H. Duyzend 2 University of Washington Abstract Understanding the genetic basis of phenotype variability in individuals with neurocognitive disorders Michael H. Duyzend Chair of the Supervisory Committee: Professor Evan E. Eichler Department of Genome Sciences Individuals with a diagnosis of a neurocognitive disorder, such as an autism spectrum disorder (ASD), can present with a wide range of phenotypes. Some have severe language and cognitive deficiencies while others are only deficient in social functioning. Sequencing studies have revealed extreme locus heterogeneity underlying the ASDs. Even cases with a known pathogenic variant, such as the 16p11.2 CNV, can be associated with phenotypic heterogeneity. In this thesis, I test the hypothesis that phenotypic heterogeneity observed in populations with a known pathogenic variant, such as the 16p11.2 CNV as well as that associated with the ASDs in general, is due to additional genetic factors. I analyze the phenotypic and genotypic characteristics of over 120 families where at least one individual carries the 16p11.2 CNV, as well as a cohort of over 40 families with high functioning autism and/or intellectual disability. In the 16p11.2 cohort, I assessed variation both internal to and external to the CNV critical region. Among de novo cases, I found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p=2.38x10-11), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome, a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p=1.14x10-2), and nine probands carrying additional CNVs disrupting autism-associated genes.
    [Show full text]
  • Quantitative Trait Loci Mapping of Macrophage Atherogenic Phenotypes
    QUANTITATIVE TRAIT LOCI MAPPING OF MACROPHAGE ATHEROGENIC PHENOTYPES BRIAN RITCHEY Bachelor of Science Biochemistry John Carroll University May 2009 submitted in partial fulfillment of requirements for the degree DOCTOR OF PHILOSOPHY IN CLINICAL AND BIOANALYTICAL CHEMISTRY at the CLEVELAND STATE UNIVERSITY December 2017 We hereby approve this thesis/dissertation for Brian Ritchey Candidate for the Doctor of Philosophy in Clinical-Bioanalytical Chemistry degree for the Department of Chemistry and the CLEVELAND STATE UNIVERSITY College of Graduate Studies by ______________________________ Date: _________ Dissertation Chairperson, Johnathan D. Smith, PhD Department of Cellular and Molecular Medicine, Cleveland Clinic ______________________________ Date: _________ Dissertation Committee member, David J. Anderson, PhD Department of Chemistry, Cleveland State University ______________________________ Date: _________ Dissertation Committee member, Baochuan Guo, PhD Department of Chemistry, Cleveland State University ______________________________ Date: _________ Dissertation Committee member, Stanley L. Hazen, MD PhD Department of Cellular and Molecular Medicine, Cleveland Clinic ______________________________ Date: _________ Dissertation Committee member, Renliang Zhang, MD PhD Department of Cellular and Molecular Medicine, Cleveland Clinic ______________________________ Date: _________ Dissertation Committee member, Aimin Zhou, PhD Department of Chemistry, Cleveland State University Date of Defense: October 23, 2017 DEDICATION I dedicate this work to my entire family. In particular, my brother Greg Ritchey, and most especially my father Dr. Michael Ritchey, without whose support none of this work would be possible. I am forever grateful to you for your devotion to me and our family. You are an eternal inspiration that will fuel me for the remainder of my life. I am extraordinarily lucky to have grown up in the family I did, which I will never forget.
    [Show full text]
  • Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
    Published OnlineFirst September 7, 2012; DOI: 10.1158/2159-8290.CD-12-0103 RESEARCH ARTICLE Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors Dalia Ercan 1 , 2 , Chunxiao Xu 1 , 3 , Masahiko Yanagita 1 , 3 , Calixte S. Monast 11 , Christine A. Pratilas 12 , 14 , Joan Montero 3 , Mohit Butaney 1 , 3 , Takeshi Shimamura 1 , 3 , 15 , Lynette Sholl 8 , Elena V. Ivanova 5 , Madhavi Tadi 12 , 14 , Andrew Rogers 1 , 3 , Claire Repellin 1 , 3 , Marzia Capelletti 1 , 3 , Ophélia Maertens 7 , 9 , Eva M. Goetz 2 , 3 , Anthony Letai 3 , Levi A. Garraway 2 , 3 , 7 , 10 , Matthew J. Lazzara 11 , Neal Rosen 13 , 14 , Nathanael S. Gray 4 , 6 , Kwok-Kin Wong 1 , 3 , 5 , 7 , and Pasi A. Jänne 1 , 3 ,5 , 7 ABSTRACT The clinical effi cacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplifi cation of mitogen-activated protein kinase 1 (MAPK1 ) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP–ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplifi cation in an erlotinib- resistant EGFR -mutant non–small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1 - amplifi ed cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy.
    [Show full text]